WO2007013868A2 - Traitement therapeutique et prophylactique antiviral topique d'adenovirus et de leurs maladies associees - Google Patents

Traitement therapeutique et prophylactique antiviral topique d'adenovirus et de leurs maladies associees Download PDF

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Publication number
WO2007013868A2
WO2007013868A2 PCT/US2005/010890 US2005010890W WO2007013868A2 WO 2007013868 A2 WO2007013868 A2 WO 2007013868A2 US 2005010890 W US2005010890 W US 2005010890W WO 2007013868 A2 WO2007013868 A2 WO 2007013868A2
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WO
WIPO (PCT)
Prior art keywords
adenovirus
ctc
subject
infection
prophylactic treatment
Prior art date
Application number
PCT/US2005/010890
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English (en)
Other versions
WO2007013868A3 (fr
Inventor
David Gershon
Original Assignee
Redox Pharmaceutical Corporation Audubon Biomedical Science And Technology Park
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/883,406 external-priority patent/US20050032739A1/en
Application filed by Redox Pharmaceutical Corporation Audubon Biomedical Science And Technology Park filed Critical Redox Pharmaceutical Corporation Audubon Biomedical Science And Technology Park
Priority to US11/097,081 priority Critical patent/US20060025398A1/en
Priority to EP05731275A priority patent/EP1784198A4/fr
Priority to CA002582311A priority patent/CA2582311A1/fr
Priority to AU2005334193A priority patent/AU2005334193A1/en
Publication of WO2007013868A2 publication Critical patent/WO2007013868A2/fr
Publication of WO2007013868A3 publication Critical patent/WO2007013868A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • Adenoviruses commonly infect the eye, respiratory and gastrointestinal tracts and can infect other organs such as the liver, urinary bladder, pancreas, central nervous system and others. There are over 50 known serotypes of Human
  • Adenovirus-related disease An example of Adenovirus-related disease [0003] Adenoviruses are the most prevalent causes of acute ocular viral disease for which there is no known cure. The actual prevalence and incidence of Epidemic Keratoconjunctivitis (EKC) caused by Adenoviruses in the US and internationally are unknown, because general practitioners and optometrists see most cases and this infection does not have to be reported to any medical authority.
  • EKC Epidemic Keratoconjunctivitis
  • EKC is highly contagious and 1 has the tendency to occur in epidemics.
  • EKC is a self-limiting disease that generally resolves within 1-3 weeks, the patient may remain highly infectious for 10-14 days or more after
  • Symptoms of EKC include conjunctival redness, swelling or redness of the eyelid, discharge from the eye, sticking together of eyelids, pain or discomfort in the eye, photophobia, or a sensation of a foreign body in the eye.
  • membranous and pseudomembranous conjunctivitis can be seen in one third of cases, which can lead to conjunctival scarring and symblepharon
  • corneal opacities can persist for weeks to months to several years (l;3). This phenomenon can decrease visual acuity significantly and cause glare symptoms (2).
  • Adenoviruses and, in particular, Adenovirus-derived keratoconjunctivitis for both therapeutic and prophylactic purposes and respiratory disease.
  • the treatment for adenovirus-derived keratoconjunctivitis, whether it be for therapeutic or prophylactic purposes, can be achieved by topical administration.
  • the treatment for respiratory disease may be by injection or by nasal administration, i.e., by spray or nose drops..
  • the expression "therapeutic treatment” means treatment for a subject already having the disease.
  • prophylactic treatment means treatment for a subject who, while not being infected by the virus, is in a situation wherein they are susceptible to or subject to the possibility of
  • CTC-96 is effective against types 1 , 2, 3, 4, 5, and 7, attesting to the effectiveness of CTC-96 against the adenovirus derived diseases outlined in Table 1. More particularly, we have
  • the word “therapeutic” means use of the inventive method to treat a subject who has already been infected with Adenovirus.
  • the word “prophylactic” means use of the inventive method to protect or decrease the likelihood of a subject who may be exposed to Adenovirus from being infected with the virus.
  • Compound CTC-96 has the structure:
  • Ri and R f are methyl, R 2 and R 2 - are hydrogen and R3 and R 3 ' are methyl,
  • CTC-96 may be prepared by the method described in the United States
  • Patent No.5, 756,491 the contents of which are hereby incorporated by reference.
  • this compound is administered topically in the form of an aqueous solution.
  • Fig. 1 is a graph of Human Adenovirus titers following exposure to
  • Fig. 2 is a graph of virus tiers after exposure of Human Adenovirus infected cells to CTC-96;
  • Fig. 3 is a graph depicting the effect of treatment of Adenovirus
  • Fig 4 is a graph depicting adenovirus titers after treatment of
  • Fig. 5 is a draft of virus titers versus drug concentration.
  • Fig. 6 is a draft of virus titers versus drug concentration.
  • Fig. 7 is a draft of virus titers versus drug concentration.
  • Fig. 8 is a draft of virus titers versus drug concentration.
  • Fig. 9 is a draft of virus titers versus drug concentration.
  • Virus dilutions were prepared from the known titers of the stock viruses (4 x 10 5 pfu/ml; 4 x 10 4 /0.1 ml) of Ad 1 Kmetz, Ad2 Wolf, Ad3 Holyfield, Ad4 Harris, , Ad7a Joseph, ATCC. This virus inoculation yielded a virus infection with an m.o.i. (multiplicity of infection) of approximately 1.0.
  • Virus was adsorbed at 37 0 C in a 5% CO 2 water-vapor atmosphere for 1 hour.
  • Viral titers were determined at each drug concentration.
  • CTC-96 has considerable advantages as an anti-viral drug: a) because of its unique mode of action it Is effective against herpes and HIV virus mutants which are resistant to currently used drugs; b) because the drug acts against two different viral targets in herpes virus the development of CTC-96-resistant mutants is deemed to be extremely rare; and c) because CTC-96 has anti-inflammatory properties its use replaces the use of steroids in herpes virus and Adenovirus therapeutics. Steroids modulate the immune response in the areas where they are applied and increase tissue susceptibility to pathogens. Efficacy Studies
  • CTC-96 Anti-adenovirus activity of CTC-96 was evaluated by standard cell culture using HeLa cells, a human cervical carcinoma immortalized cell line (the usual host for laboratory grade adenovirus) and anti-viral plaque-reduction assays.
  • CTC-96 has an inhibitory (prophylactic) effect on growth when virus is exposed to
  • Fig. 1 shows Adenovirus type 5 titers following direct exposure of the virus to CTC-96 prior to HeLa cell infection.
  • Fig. 1 The data graphically depicted in Fig. 1 were obtained as follows: varying concentrations of the CTC-96 were mixed with concentrated Human Adenovirus, [Adenovirus type 5 (Ad5)] and incubated at 37° C for 60 minutes. Aliquots were then diluted 500 fold into growth medium. HeIa cells were exposed to
  • CTC-96 also has a potentially therapeutic effect as can be seen by inhibition of viral growth in Adenovirus infected cells, which are subsequently exposed to the drug.
  • Fig. 2 shows virus titers obtained after exposure of human Adenovirus type 5 (Ad5) infected HeLa cells to CTC-96. These data were obtained as follows: Adenovirus was adsorbed onto HeLa cell monolayers for 60 min at 37%; serial dilutions of CTC-96 were overlaid onto the minelayers. Monolayers were then incubated for 24 hr at 37 0 C and 5% C02.
  • rabbits were infected with Human Adenovirus Type 5 by the installation 10 ⁇ pfu
  • adenovirus according to our protocol of conjunctival and corneal scarification for the
  • Fig. 4 shows adenovirus titers after treatment of rabbit eyes with CTC-96 or placebo. These data were obtained by the following procedure: rabbits were infected with Human Adenovirus Type 5 by the installation 10 6 pfu adenovirus according to our protocol of conjunctival and corneal scarification for the production of Keratoconjunctivitis. On day 8 post-inoculation treatment with eye drops containing CTC-96 or placebo was initiated. Adenovirus recovery from tear film was evaluated by plaque assay on confluent HeLa cell monolayers. Data are presented as Average ⁇ SD.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Otolaryngology (AREA)
  • Engineering & Computer Science (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Biotechnology (AREA)
  • Pulmonology (AREA)
  • AIDS & HIV (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne une méthode pour le traitement thérapeutique et prophylactique d'adénovirus. En particulier, l'invention concerne une méthode pour le traitement thérapeutique d'un adénovirus chez un sujet, laquelle méthode consistant à administrer de manière topique une quantité efficace d'antiviral de CTC-96 au patient. En outre, l'invention concerne une méthode pour le traitement prophylactique d'une infection provoquée par un adénovirus chez un patient, laquelle méthode consistant à administrer une quantité efficace prophylactiquement anti-andénovirus de CTC-96 au patient, pour minimiser la probabilité d'infection du patient par l'adénovirus.
PCT/US2005/010890 2003-06-30 2005-03-31 Traitement therapeutique et prophylactique antiviral topique d'adenovirus et de leurs maladies associees WO2007013868A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US11/097,081 US20060025398A1 (en) 2003-06-30 2005-03-31 Topical antiviral therapeutic and prophylactic treatment of adenoviruses and their associated diseases
EP05731275A EP1784198A4 (fr) 2004-06-30 2005-03-31 Traitement therapeutique et prophylactique antiviral topique d'adenovirus et de leurs maladies associees
CA002582311A CA2582311A1 (fr) 2004-06-30 2005-03-31 Traitement therapeutique et prophylactique antiviral topiqued'adenovirus et de leurs maladies associees
AU2005334193A AU2005334193A1 (en) 2004-06-30 2005-03-31 Topical antiviral therapeutic and prophylactic treatment of adenoviruses and their associated diseases

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10/883,406 2004-06-30
US10/883,406 US20050032739A1 (en) 2003-06-30 2004-06-30 Topical antiviral therapeutic and prophylactic treatment of adenoviruses and their associated diseases
US11/097,081 US20060025398A1 (en) 2003-06-30 2005-03-31 Topical antiviral therapeutic and prophylactic treatment of adenoviruses and their associated diseases
US11/097,081 2005-03-31

Publications (2)

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WO2007013868A2 true WO2007013868A2 (fr) 2007-02-01
WO2007013868A3 WO2007013868A3 (fr) 2007-04-26

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US (1) US20060025398A1 (fr)
EP (1) EP1784198A4 (fr)
AU (1) AU2005334193A1 (fr)
CA (1) CA2582311A1 (fr)
WO (1) WO2007013868A2 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991015212A1 (fr) 1990-03-30 1991-10-17 Chai-Tech Corporation Compositions antivirales et leur procede d'utilisation
US5756491A (en) 1986-05-13 1998-05-26 Chai-Tech Corporation Antiviral cobalt-organic compounds
WO1999056552A1 (fr) 1998-05-06 1999-11-11 The Children's Hospital Research Foundation Methode de traitement prophylactique de l'infection a hsv
WO2001005396A1 (fr) 1999-07-16 2001-01-25 The Trustees Of Columbia University In The City Of New York Utilisation de chelates de cobalts pour le traitement ou la prevention de l'infection virale

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040157920A1 (en) * 1999-06-11 2004-08-12 Stewart Claudia Cherney Method of adenovirus, HIV and HPV prophylaxis
US6756368B1 (en) * 1999-07-16 2004-06-29 The Trustees Of Columbia University In The City Of New York Use of cobalt chelates for treating or preventing virus infection

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5756491A (en) 1986-05-13 1998-05-26 Chai-Tech Corporation Antiviral cobalt-organic compounds
WO1991015212A1 (fr) 1990-03-30 1991-10-17 Chai-Tech Corporation Compositions antivirales et leur procede d'utilisation
WO1999056552A1 (fr) 1998-05-06 1999-11-11 The Children's Hospital Research Foundation Methode de traitement prophylactique de l'infection a hsv
WO2001005396A1 (fr) 1999-07-16 2001-01-25 The Trustees Of Columbia University In The City Of New York Utilisation de chelates de cobalts pour le traitement ou la prevention de l'infection virale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1784198A4

Also Published As

Publication number Publication date
WO2007013868A3 (fr) 2007-04-26
AU2005334193A1 (en) 2007-02-22
EP1784198A2 (fr) 2007-05-16
CA2582311A1 (fr) 2007-02-01
US20060025398A1 (en) 2006-02-02
EP1784198A4 (fr) 2008-01-23
AU2005334193A8 (en) 2008-12-18

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